Multi-Electrode Apposition Judgment Using Pressure Elements

ABSTRACT

Apparatus and methods for determining positioning of a energy delivery element include deploying a energy delivery element at a treatment site proximal to a vessel wall; using a multi-region pressure sensing apparatus to sense pressures applied in a plurality of directions about the energy delivery element; and determining an orientation of the energy delivery element based on the pressures measured in the plurality of directions about the energy delivery element.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/338,156, titled “Multi-Electrode Apposition Judgment Using PressureElements,” filed on Oct. 28, 2016, which is a continuation of U.S.patent application Ser. No. 14/716,167, titled “Multi-ElectrodeApposition Judgment Using Pressure Elements,” filed May 19, 2015, nowU.S. Pat. No. 9,510,773, which is a continuation of U.S. patentapplication Ser. No. 13/870,172, titled “Multi-Electrode AppositionJudgment Using Pressure Elements,” filed Apr. 25, 2013, now U.S. Pat.No. 9,066,726, which claims the benefit of and priority to U.S.Provisional Application No. 61/801,890, titled “MULTI-ELECTRODEAPPOSITION JUDGMENT USING PRESSURE ELEMENTS,” filed Mar. 15, 2013, theentirety of these applications is hereby incorporated by referenceherein.

TECHNICAL FIELD

The present disclosure relates generally to the field ofneuromodulation, and some embodiments relate to measurements and metricsfor determining the efficacy of treatment. More particularly, someembodiments relate to the use of pressure sensors to determinepositioning of neuromodulation devices and to determine theeffectiveness of renal neuromodulation treatment.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS innervate tissue present in almost every organ system of the humanbody and can affect characteristics such as pupil diameter, gutmotility, and urinary output. Such regulation can have adaptive utilityin maintaining homeostasis or preparing the body for rapid response toenvironmental factors. Chronic activation of the SNS, however, is acommon maladaptive response that can drive the progression of manydisease states. Excessive activation of the renal SNS in particular hasbeen identified experimentally in humans as a likely contributor to thecomplex pathophysiology of hypertension, states of volume overload (suchas heart failure), and progressive renal disease. For example,radiotracer dilution has demonstrated increased renal norepinephrine(“NE”) spillover rates in patients with essential hypertension.

Cardio-renal sympathetic nerve hyperactivity can be particularlypronounced in patients with heart failure. For example, an exaggeratedNE overflow from the heart and kidneys of plasma is often found in thesepatients. Heightened SNS activation commonly characterizes both chronicand end stage renal disease. In patients with end stage renal disease,NE plasma levels above the median have been demonstrated to bepredictive of cardiovascular diseases and several causes of death. Thisis also true for patients suffering from diabetic or contrastnephropathy. Evidence suggests that sensory afferent signals originatingfrom diseased kidneys are major contributors to initiating andsustaining elevated central sympathetic outflow.

Sympathetic nerves innervating the kidneys terminate in the bloodvessels, the juxtaglomerular apparatus, and the renal tubules.Stimulation of the renal sympathetic nerves can cause increased reninrelease, increased sodium (Na+) reabsorption, and a reduction of renalblood flow. These neural regulation components of renal function areconsiderably stimulated in disease states characterized by heightenedsympathetic tone and likely contribute to increased blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome (i.e., renal dysfunction as a progressive complication ofchronic heart failure). Pharmacologic strategies to thwart theconsequences of renal efferent sympathetic stimulation include centrallyacting sympatholytic drugs, beta blockers (intended to reduce reninrelease), angiotensin converting enzyme inhibitors and receptor blockers(intended to block the action of angiotensin II and aldosteroneactivation consequent to renin release), and diuretics (intended tocounter the renal sympathetic mediated sodium and water retention).These pharmacologic strategies, however, have significant limitationsincluding limited efficacy, compliance issues, side effects, and others.Recently, intravascular devices that reduce sympathetic nerve activityby applying an energy field to a target site in the renal artery (e.g.,via radiofrequency ablation) have been shown to reduce blood pressure inpatients with treatment-resistant hypertension.

SUMMARY

The present technology is generally directed to modulation of nerves,including nerves innervating the kidneys. Various techniques can be usedto partially or completely incapacitate neural pathways, such as thoseinnervating the kidney. The application of energy to tissue can inducethe desired treatment effects. The energy can be, for example,radiofrequency energy, mechanical energy, acoustic energy, electricalenergy, thermal energy, and so on. The energy can be delivered to thetissue by one or more electrodes or other energy delivery elements. Theenergy delivery elements can be disposed on a support structure and thesupport structure used to position the energy delivery elements fortreatment.

In various embodiments, one or more pressure sensors are provided anddisposed adjacent the one or more energy delivery elements. The pressuresensors can be used to measure attributes such as blood pressure, bloodflow and pressure of energy delivery elements against a vessel wall.Multi-region sensors can be used to detect pressures in a plurality ofdirections.

In other embodiments, an apparatus for neuromodulation treatment caninclude a therapeutic assembly configured to be delivered to a treatmentsite within a vessel; an energy delivery element disposed on thetherapeutic assembly and configured to be positioned against a vesselwall to deliver neuromodulation energy at the treatment site; and apressure sensor disposed adjacent and in fixed relation to the energydelivery element and comprising a plurality of pressure sensitiveregions. A pressure measurement circuit can also be included and coupledto the pressure sensor and configured to determine which of theplurality of pressure sensitive regions is being subjected to increasedpressure.

In some embodiments, the plurality of pressure sensitive regions can bearranged to sense pressure in a plurality of radial directions relativeto the energy delivery element. The plurality of pressure sensitiveregions can also be configured to allow the pressure sensor to respondto pressure applied at different angles, and the apparatus can furtherinclude a pressure measurement circuit coupled to the pressure sensorand configured to determine an angle of apposition of the energydelivery element.

In some applications, the pressure sensor can include a first conductiveannular ring; a second conductive annular ring disposed coaxially withthe first conductive annular ring; a plurality of non-conductive areason the second conductive annular ring, the non-conductive areas definingconductive regions about the second conductive annular ring. Thenon-conductive areas can include slots disposed in the second conductiveannular ring, and the conductive regions can be spaced evenly about thesecond conductive annular ring.

The pressure sensor can include: a first hollow conductive member; asecond hollow conductive member disposed coaxially within the firstconductive member; a plurality of non-conductive areas on the firstconductive member, the non-conductive areas defining conductive regionsabout the first conductive member, wherein the non-conductive areascomprise slots disposed first conductive member. The first and secondhollow conductive members can be annular in shape.

In various embodiments, the energy delivery element can be an RFelectrode, a thermal element, a cryo-ablation element, a microwaveenergy delivery element, an optical energy delivery element, or anultrasonic transducer. The therapeutic assembly can include an elongatedsupport structure configured to take a pre-determined shape upondeployment in a vessel, wherein the energy delivery element can bedisposed in a predetermined orientation on the elongated supportstructure, and wherein the pressure sensor can be arranged such that theplurality of pressure sensitive regions can be configured to sensepressure in a plurality of directions about the energy delivery element.The elongated support structure can be a shape set wire set in a helicalgeometry or a catheter tip, for example.

In further embodiments, a method for determining positioning an energydelivery element for neuromodulation, can include deploying an energydelivery element at a treatment site proximal to a vessel wall; using amulti-region pressure sensing apparatus to sense pressures applied in aplurality of directions about the energy delivery element; anddetermining an orientation of the energy delivery element based on thepressures measured in the plurality of directions about the energydelivery element. Determining an orientation, can include measuringpressures applied against a plurality of pressure sensors in themulti-region pressure sensing apparatus, each sensor disposed to measurepressure impinging on the sensing apparatus at a different angle;determining based on the pressures measured which of a plurality ofregions of the pressure sensing apparatus can be contacting the vesselwall; and determining an orientation of the energy delivery elementbased on the determination of which region of the pressure sensingapparatus can be contacting the vessel wall.

The method can include providing feedback to an operator to inform theoperator when contact is made with the vessel based on sensed pressuresand to inform the operator of the orientation of the energy deliveryelement.

In some embodiments, the multi-region pressure sensing apparatus caninclude: a first hollow conductive member; a second hollow conductivemember disposed coaxially within the first conductive member; aplurality of non-conductive areas on the first conductive member, thenon-conductive areas defining conductive regions about the firstconductive member. In other embodiments, the multi-region pressuresensing apparatus includes: a first conductive annular ring; a secondconductive annular ring disposed coaxially with the first conductiveannular ring; a plurality of non-conductive areas on the secondconductive annular ring, the non-conductive areas defining conductiveregions about the second conductive annular ring.

In still further embodiments, an apparatus for neuromodulationtreatment, can include a support structure configured to be delivered toa treatment site within a vessel; a plurality of energy deliveryelements disposed on the support structure and configured to bepositioned against a vessel wall to deliver neuromodulation energy atthe treatment site; and a plurality of pressure sensor elements disposedadjacent and in fixed relation to the energy delivery elements, eachpressure sensor element can include a plurality of pressure sensitiveregions.

Other features and aspects of the disclosed technology will becomeapparent from the following detailed description, taken in conjunctionwith the accompanying drawings, which illustrate, by way of example, thefeatures in accordance with embodiments of the disclosed technology. Thesummary is not intended to limit the scope of any inventions describedherein, which are defined solely by the claims attached hereto.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention, in accordance with one or more variousembodiments, is described in detail with reference to the accompanyingfigures. The drawings are provided for purposes of illustration only andmerely depict typical or example embodiments of the invention. Thesedrawings are provided to facilitate the reader's understanding of thesystems and methods described herein, and shall not be consideredlimiting of the breadth, scope, or applicability of the claimedinvention.

FIG. 1 illustrates a system in accordance with one embodiment of thetechnology disclosed herein.

FIG. 2 illustrates one example of modulating renal nerves with anembodiment of the system described with reference to FIG. 1.

FIG. 3 illustrates a cross-sectional view of one embodiment of atherapeutic assembly defining a helical support structure in a deliverystate within a renal artery.

FIG. 4 illustrates the example therapeutic assembly 21 of FIG. 3 in anexpanded state within the renal artery.

FIG. 5 is a diagram illustrating an example pressure measurement devicein accordance with one embodiment of the technology disclosed herein.

FIG. 6A illustrates an example of a pressure measurement deviceelectrically connected to a measuring circuit in accordance with oneembodiment of the technology disclosed herein.

FIG. 6B is a diagram illustrating an example of a circuit that can beused to measure changes in capacitance in accordance with one embodimentof the technology disclosed herein.

FIG. 6C is a diagram illustrating another exemplary circuit that can beused to measure changes in capacitance in accordance with one embodimentof the technology disclosed herein.

FIGS. 7A-7D provide examples of the application of one or more pressuremeasurement devices proximal to a therapeutic assembly to providepressure measurements in accordance with embodiments of the technologydisclosed herein.

FIGS. 8A-8C provide example applications of pressure measurement devicesin accordance with one embodiment of the technology disclosed herein.

FIG. 9 is a diagram illustrating an example of a pressure sensorintegrated within an electrode in accordance with one embodiment of thetechnology described herein.

FIG. 10A is a diagram illustrating an example of a support structurewith a plurality of energy delivery elements.

FIG. 10B is a diagram illustrating an example in which a plurality ofpressure measurement devices are disposed on a support structureproximal to a plurality of electrodes in accordance with one embodimentof the technology disclosed herein.

FIG. 11 provides a cross-sectional view of a pressure measurement devicemounted circumferentially about a support structure in accordance withone embodiment of the technology disclosed herein.

FIG. 12 is an operational flow diagram illustrating an example processfor using a pressure sensor to determine placement in accordance withone embodiment of the technology disclosed herein.

FIG. 13 is a diagram illustrating an example process for using feedbackto determine the effectiveness of treatment in accordance with oneembodiment of the systems and methods described herein.

FIG. 14 illustrates an example computing module that may be used inimplementing various features of embodiments of the systems and methodsdisclosed herein.

FIG. 15, illustrates a network of nerves that make up the sympatheticnervous system, allowing the brain to communicate with the body.

FIG. 16, illustrates the kidney, innervated by the renal plexus (RP),which is intimately associated with the renal artery.

FIGS. 17A and 178, illustrate afferent communication from the kidney tothe brain and from one kidney to the other kidney (via the centralnervous system).

FIG. 18A shows human arterial vasculature.

FIG. 18B shows human venous vasculature.

The figures are not intended to be exhaustive or to limit the inventionto the precise form disclosed. It should be understood that theinvention can be practiced with modification and alteration, and thatthe invention be limited only by the claims and the equivalents thereof.

DESCRIPTION

The present technology is generally directed to modulation of nerves,including nerves innervating the kidneys. Various techniques can be usedto partially or completely incapacitate neural pathways, such as thoseinnervating the kidney. The purposeful application of energy (e.g.,radiofrequency energy, mechanical energy, acoustic energy, electricalenergy, thermal energy, etc.) to tissue can induce one or more desiredthermal heating effects on localized regions of the renal artery andadjacent regions of the renal plexus (RP), which lay intimately withinor adjacent to the adventitia of the renal artery. The purposefulapplication of the thermal heating and cooling effects can achieveneuromodulation along all or a portion of the renal plexus (RP).

Specific details of several embodiments of the present technology aredescribed herein with reference to the accompanying figures. Althoughmany of the embodiments are described herein with respect tocryotherapeutic, electrode-based, transducer-based, and chemical-basedapproaches, other treatment modalities in addition to those describedherein are within the scope of the present technology. Additionally,other embodiments of the present technology can have configurations,components, or procedures different from those described herein. Forexample, other embodiments can include additional elements and featuresbeyond those described herein or be without several of the elements andfeatures shown and described herein. Generally, unless the contextindicates otherwise, the terms “distal” and “proximal” within thisdisclosure reference a position relative to an operator or an operator'scontrol device. For example, “proximal” can refer to a position closerto an operator or an operator's control device, and “distal” can referto a position that is more distant from an operator or an operator'scontrol device. The headings provided herein are for convenience only.

I. Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the kidneys. In particular,renal neuromodulation comprises inhibiting, reducing, and/or blockingneural communication along neural fibers (i.e., efferent and/or afferentnerve fibers) innervating the kidneys. Such incapacitation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).Renal neuromodulation is expected to efficaciously treat severalclinical conditions characterized by increased overall sympatheticactivity, and in particular conditions associated with centralsympathetic overstimulation such as hypertension, heart failure, acutemyocardial infarction, metabolic syndrome, insulin resistance, diabetes,left ventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,osteoporosis and sudden death. The reduction of afferent neural signalscontributes to the systemic reduction of sympathetic tone/drive, andrenal neuromodulation is expected to be useful in treating severalconditions associated with systemic sympathetic overactivity orhyperactivity. Renal neuromodulation can potentially benefit a varietyof organs and bodily structures innervated by sympathetic nerves. Forexample, a reduction in central sympathetic drive may reduce insulinresistance that afflicts patients with metabolic syndrome and Type IIdiabetics.

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. The purposefulapplication of energy (e.g., electrical energy, thermal energy) totissue by energy delivery element(s) can induce one or more desiredthermal heating effects on localized regions of the renal artery andadjacent regions of the renal plexus RP, which lay intimately within oradjacent to the adventitia of the renal artery. The purposefulapplication of the thermal heating effects can achieve neuromodulationalong all or a portion of the renal plexus RP.

The thermal heating effects can include both thermal ablation andnon-ablative thermal alteration or damage (e.g., via sustained heatingand/or resistive heating). Desired thermal heating effects may includeraising the temperature of target neural fibers above a desiredthreshold to achieve non-ablative thermal alteration, or above a highertemperature to achieve ablative thermal alteration. For example, thetarget temperature can be above body temperature (e.g., approximately37° C.) but less than about 45° C. for non-ablative thermal alteration,or the target temperature can be about 45° C. or higher for the ablativethermal alteration.

More specifically, exposure to thermal energy (heat) in excess of a bodytemperature of about 37° C., but below a temperature of about 45° C.,may induce thermal alteration via moderate heating of the target neuralfibers or of vascular structures that perfuse the target fibers. Incases where vascular structures are affected, the target neural fibersare denied perfusion resulting in necrosis of the neural tissue. Forexample, this may induce non-ablative thermal alteration in the fibersor structures. Exposure to heat above a temperature of about 45° C., orabove about 60° C., may induce thermal alteration via substantialheating of the fibers or structures. For example, such highertemperatures may thermally ablate the target neural fibers or thevascular structures. In some patients, it may be desirable to achievetemperatures that thermally ablate the target neural fibers or thevascular structures, but that are less than about 90° C., or less thanabout 85° C., or less than about 80° C., and/or less than about 75° C.Regardless of the type of heat exposure utilized to induce the thermalneuromodulation, a reduction in renal sympathetic nerve activity(“RSNA”) is expected.

II. Selected Embodiments of Treatment Systems

FIG. 1 illustrates a system 1 in accordance with an embodiment of thepresent technology. The system 1 includes a renal neuromodulation system10 (“system 10”). The system 10 includes an intravascular orintraluminal treatment device 12 that is operably coupled to an energysource or console 26. Energy source or console 26 can include, forexample, an RF energy generator, a cryotherapy console, an ultrasonicsignal generator or other energy source. Energy source or console 26 canalso include a source of drugs or other substances used for chemicalneuromodulation. In the embodiment shown in FIG. 1, the treatment device12 (e.g., a catheter) includes an elongated shaft 16 having a proximalportion 18, a handle 34 at a proximal region of the proximal portion 18,and a distal portion 20 extending distally relative to the proximalportion 18. The treatment device 12 further includes a therapeuticassembly or treatment section 21 at the distal portion 20 of the shaft16. The therapeutic assembly 21 can include a neuromodulation assembly(e.g., actuators such as one or more electrodes or energy deliveryelements, a cryotherapeutic cooling assembly, etc.). The therapeuticassembly 21 can include virtually any suitable energy delivery deviceconfigured to cause therapeutically effective nerve modulation, such ascryotherapeutic catheters, single- or multi-electrode neuromodulationdevices, or ultrasound transducers.

As explained in further detail below, and as shown in the insert of FIG.1, the therapeutic assembly 21 in some embodiments can include an arrayof two or more electrodes or energy delivery elements 24 configured tobe delivered to a renal blood vessel (e.g., a renal artery) in alow-profile configuration. Upon delivery to the target treatment sitewithin the renal blood vessel, the therapeutic assembly 21 is furtherconfigured to be deployed into an expanded state (e.g., a generallyhelical or spiral configuration as shown in the insert) for deliveringenergy at the treatment site and providing therapeutically-effectiveelectrically- and/or thermally induced renal neuromodulation.Alternatively, the deployed state may be non-helical provided that thedeployed state delivers the energy to the treatment site.

In some embodiments, the therapeutic assembly 21 may be placed ortransformed into the deployed state or arrangement via remote actuation,e.g., via an actuator 36, such as a knob, button, pin, or lever carriedby the handle 34. In other embodiments, however, the therapeuticassembly 21 may be transformed between the delivery and deployed statesusing other suitable mechanisms or techniques.

The proximal end of the therapeutic assembly 21 is carried by or affixedto the distal portion 20 of the elongated shaft 16. A distal end of thetherapeutic assembly 21 may terminate with, for example, an atraumaticrounded tip or cap. Alternatively, the distal end of the therapeuticassembly 21 may be configured to engage another element of the system 10or treatment device 12. For example, the distal end of the therapeuticassembly 21 may define a passageway for engaging a guide wire (notshown) for delivery of the treatment device using over-the-wire (“OTW”)or rapid exchange (“RX”) techniques.

The energy source or console 26 is configured to generate a selectedform and magnitude of energy for delivery to the target treatment sitevia the therapeutic assembly 21. Particularly, in some embodiments, anRF energy generator can be configured to generate a selected form andmagnitude of energy for delivery to the target treatment site via theenergy delivery elements 24. The energy generator 26 can be electricallycoupled to the treatment device 12 via a cable 28. At least one supplywire (not shown) passes along the elongated shaft 16 or through a lumenin the elongated shaft 16 to the energy delivery elements 24 andtransmits the treatment energy to the energy delivery elements 24. Insome embodiments, each energy delivery element 24 includes its ownsupply wire. In other embodiments, however, two or more energy deliveryelements 24 may be electrically coupled to the same supply wire.

A control mechanism, such as foot pedal 32 or other operator control,may be connected (e.g., pneumatically connected or electricallyconnected) to the console to allow the operator to initiate, terminateand, optionally, adjust various operational characteristics of theenergy generator, including, but not limited to, power delivery.

The system 10 may also include a remote control device (not shown) thatcan be positioned in a sterile field and operably coupled to thetherapeutic assembly 21. The remote control device can be configured toallow for selective activation of the therapeutic assembly 21, such asselectively turning off and on energy delivery elements 24. For example,the remote control device can be configured to allow the operator toinitiate, terminate and, optionally, adjust various operationalcharacteristics of the energy generator. In some embodiments, a controlmechanism (not shown) may be built into the handle assembly 34 allowingoperator control through actuation of buttons, switches or othermechanisms on the handle assembly 34.

In some embodiments, the system 10 may be configured to provide deliveryof a monopolar electric field via the energy delivery elements 24. Insuch embodiments, a neutral or dispersive electrode 38 may beelectrically connected to the energy generator 26 and attached to theexterior of the patient (as shown in FIG. 2). Additionally, one or moresensors (not shown), such as one or more temperature (e.g.,thermocouple, thermistor, etc.), impedance, pressure, optical, flow,chemical or other sensors, may be located proximate to or within theenergy delivery elements 24 and connected to one or more supply wires(not shown). For example, a total of two supply wires may be included,in which both wires could transmit the signal from the sensor and onewire could serve dual purpose and also convey the energy to the energydelivery elements 24. Alternatively, a different number of supply wiresmay be used to transmit energy to the energy delivery elements 24.

The energy source 26 can be configured to deliver the treatment energyunder the control of an automated control algorithm 30, under thecontrol of the clinician, or via a combination thereof. In addition, theenergy source or console 26 may include one or more evaluation orfeedback algorithms 31 that can be configured to accept information andprovide feedback to the clinician before, during, and/or after therapy(e.g., neuromodulation). Feedback can be provided in the form ofaudible, visual or haptic feedback. The feedback can be based on outputfrom a monitoring system (not shown). The monitoring system can be asystem including sensors or other monitoring devices integrated withtreatment device 12, sensors or other monitoring devices separate fromtreatment device 12, or a combination thereof. The monitoring devices ofthe monitoring system can be configured to measure conditions at thetreatment site (e.g., the temperature of the tissue being treated),systemic conditions (e.g., patient vital signs), or other conditionsgermane to the treatment or to the health and safety of the patient.

The energy source 26 can further include a device or module that mayinclude processing circuitry, such as one or more microprocessors andassociated memory. The processing circuitry may be configured to executestored instructions relating to the control algorithm 30, theevaluation/feedback algorithm 31 and other functions of the device. Theenergy source 26 may be configured to communicate with the treatmentdevice 12 (e.g., via the cable 28) to control the neuromodulationassembly and/or to send signals to or receive signals from themonitoring system. The display 33 may be configured to provideindications of power levels or sensor data, such as audio, visual orother indications, or may be configured to communicate the informationto another device. For example, the console 26 may also be operablycoupled to a catheter lab screen or system for displaying treatmentinformation (e.g., nerve activity before and after treatment, effects ofablation, efficacy of ablation of nerve tissue, lesion location, lesionsize, etc.).

The energy source or console 26 can be configured to control, monitor,supply, or otherwise support operation of the treatment device 12. Inother embodiments, the treatment device 12 can be self-contained and/orotherwise configured for operation without connection to the energysource or console 26. As shown in the example of FIG. 1, the energysource or console 26 can include a primary housing having a display 33.

Furthermore, the energy source or console 26 can be configured tocommunicate with the treatment device 12, e.g., via the cable 28. Forexample, the therapeutic assembly 21 of the treatment device 12 caninclude a sensor (not shown) (e.g., a recording electrode, a temperaturesensor, a pressure sensor, or a flow rate sensor) and a sensor lead (notshown) (e.g., an electrical lead or a pressure lead) configured to carrya signal from the sensor to the handle 34. The cable 28 can beconfigured to carry the signal from the handle 34 to the energy sourceor console 26.

The energy source or console 26 can have different configurationsdepending on the treatment modality of the treatment device 12. Forexample, when the treatment device 12 is configured for electrode-basedor transducer-based treatment, the energy source or console 26 caninclude an energy generator (not shown) configured to generate RFenergy, pulsed RF energy, microwave energy, optical energy, focusedultrasound energy (e.g., high-intensity focused ultrasound energy),direct heat energy, or another suitable type of energy. In someembodiments, the energy source or console 26 can include a RF generatoroperably coupled to one or more electrodes (not shown) of thetherapeutic assembly 21.

As a further example, in embodiments where the treatment device 12 isconfigured for cryotherapeutic treatment, the energy source or console26 can include a refrigerant reservoir (not shown) and can be configuredto supply the treatment device 12 with refrigerant, e.g., pressurizedrefrigerant in liquid or substantially liquid phase. Similarly, inembodiments where the treatment device 12 is configured forchemical-based treatment, the energy source or console 26 can include achemical reservoir (not shown) and can be configured to supply thetreatment device 12 with the chemical. In some embodiments, thetreatment device 12 can include an adapter (not shown) (e.g., a luerlock) configured to be operably coupled to a syringe (not shown). Theadapter can be fluidly connected to a lumen (not shown) of the treatmentdevice 20, and the syringe can be used, for example, to manually deliverone or more chemicals to the treatment location, to withdraw materialfrom the treatment location, to inflate a balloon (not shown) of thetherapeutic assembly 21, to deflate a balloon of the therapeuticassembly 21, or for another suitable purpose. In other embodiments, theenergy source or console 26 can have other suitable configurations.

FIG. 2 illustrates one example of modulating renal nerves with anembodiment of the system 10. In this embodiment, the treatment device 12provides access to the renal plexus (RP) through an intravascular path(P), such as a percutaneous access site in the femoral (illustrated),brachial, radial, or axillary artery to a targeted treatment site withina respective renal artery (RA). As illustrated, a section of theproximal portion 18 of the shaft 16 is exposed externally of thepatient. By manipulating the proximal portion 18 of the shaft 16 fromoutside the intravascular path (P), the clinician may advance the shaft16 through the sometimes tortuous intravascular path (P) and remotelymanipulate the distal portion 20 of the shaft 16. Image guidance, e.g.,computed tomography (CT), fluoroscopy, intravascular ultrasound (IVUS),optical coherence tomography (OCT), or another suitable guidancemodality, or combinations thereof, may be used to aid the clinician'smanipulation. Further, in some embodiments, image guidance components(e.g., IVUS, OCT) may be incorporated into the treatment device 12itself.

After the therapeutic assembly 21 is adequately positioned in the renalartery (RA), it can be radially expanded or otherwise deployed using thehandle 34 or other suitable means until the neuromodulation assembly(e.g., energy delivery elements 24) is positioned at its target site instable contact with the inner wall of the renal artery (RA). Thepurposeful application of energy from the neuromodulation assembly(e.g., from energy delivery elements 24) is then applied to tissue toinduce one or more desired neuromodulating effects on localized regionsof the renal artery and adjacent regions of the renal plexus (RP), whichlay intimately within, adjacent to, or in close proximity to theadventitia of the renal artery (RA). The purposeful application of theenergy may achieve neuromodulation along all or at least a portion ofthe renal plexus (RP).

The neuromodulating effects are generally a function of, at least inpart, power, time, contact between the energy delivery elements 24 andthe vessel wall, and blood flow through the vessel. The neuromodulatingeffects may include denervation, thermal ablation, and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating).

The energy delivery elements of the therapeutic assembly 21 may beproximate to, adjacent to, or carried by (e.g., adhered to, threadedover, wound over, and/or crimped to) a support structure. In someembodiments, the therapeutic assembly 21 defines a substantially helicalsupport structure that can be delivered to the treatment site in alow-profile or collapsed state, and expanded at the treatment site tocontact the renal artery wall along a helical path. One example of ahelical support structure includes a pre-shaped helical section woundaround a central lumen. A straightening guide wire can be provided andinserted into the lumen to force the helical section into astraightened, delivery configuration. Withdrawal of the guide wireallows the helical section to expand making contact with vessel walls.

FIGS. 3 and 4 illustrate an example embodiment in which the supportstructure is in a helical configuration. FIG. 3 is a cross-sectionalview illustrating one embodiment of therapeutic assembly 21 defining ahelical support structure in a delivery state (e.g., low-profile orcollapsed configuration) within a renal artery RA. FIG. 4 illustratesthis example therapeutic assembly 21 in an expanded state (e.g.,expanded or helical configuration) within the renal artery RA.

Referring first to FIG. 3, the delivery arrangement of the therapeuticassembly 21 defines a low profile about the longitudinal axis A-A of theassembly such that a transverse dimension of the therapeutic assembly 21is sufficiently small to define a clearance distance between an arterialwall 55 and the treatment device 12. The delivery state facilitatesinsertion and/or removal of the treatment device 12 and, if desired,repositioning of the therapeutic assembly 21 within the renal artery RA.In the collapsed configuration, for example, the geometry of the supportstructure 22 facilitates movement of the therapeutic assembly 21 througha guide catheter 90 to the treatment site in the renal artery RA.

After locating the therapeutic assembly 21 in the renal artery RA, thetherapeutic assembly 21 is transformed from its delivery state to itsdeployed state or deployed arrangement. As shown in FIG. 4, therapeuticassembly 21 is expanded within the renal artery RA such that the energydelivery elements 24 are in contact with the renal artery wall 55. Insome embodiments, manipulation of the distal portion 20 also facilitatescontact between the energy delivery elements 24 and the wall of therenal artery.

Alignment of the assembly may include alignment of geometrical aspectsof the energy delivery elements 24 with the renal artery wall 55. Forexample, in embodiments in which the energy delivery elements 24 have acylindrical shape with rounded ends, alignment may include alignment ofthe longitudinal surface of the individual energy delivery elements 24with the artery wall 55. In another example, an embodiment may compriseenergy delivery elements 24 having a structured shape or inactivesurface, and alignment may include aligning the energy delivery elements24 such that the structured shape or inactive surface is not in contactwith the artery wall 55. In yet another example, an embodiment maycomprise energy delivery elements 24 having a relatively flat energydelivery surface, and alignment may include aligning the energy deliveryelements 24 such that the flat energy delivery surface is in stablecontact with the artery wall 55.

Examples of helical support structures 22 that are suitable for use withthe disclosed technology are described in more detail in U.S. patentapplication Ser. No. 13/281,360, filed Oct. 25, 2011; U.S. patentapplication Ser. No. 13/281,361, filed Oct. 25, 2011; and U.S. patentapplication Ser. No. 13/281,395, filed Oct. 25, 2011, each of which areincorporated by reference herein in their entirety.

One feature of the expanded therapeutic assembly 21 in the helicalconfiguration is that the energy delivery elements 24 associated withthe helical structure may be placed into stable contact with a vesselwall to reliably create consistent lesions. The orientation and pressureof the helical support structure 22 may be assessed in vivo by one ormore pressure transducers, as discussed more fully below.

In various embodiments, one or more sensors can be included with ordisposed on support structure 22 to sense conditions before, during andafter renal neuromodulation. For example, pressure sensors, temperaturesensors, flow sensors and the like can be included. In some embodiments,for example, a multi-region pressure sensing apparatus can be used tomeasure pressure impinging on the device at different angles. Such amulti-region pressure sensing apparatus can include a plurality ofindividual pressure sensors (or different pressure sensing regions)disposed about a central body so that each sensor (e.g., region)measures pressure impinging on the device at a different angle. A fewexamples of such intra-vascular pressure measurement devices are nowdescribed.

One such exemplary device is illustrated in FIG. 5. The pressuremeasurement device 70 illustrated in FIG. 5 comprises two annular rings72, 74 assembled in a coaxial configuration forming a hollow cylindricalunit. Inner annular ring 72 is made of a conductive material forming acontinuous or substantially continuous annular ring. Outer annular ring74 is also made of a conductive material forming an annular ring havinga diameter greater than that of inner annular ring. Inner and outerannular rings 72, 74, are separated from each other by a distance, D. Inone embodiment, distance D is constant about the circumference of theannular rings 72, 74, while in other embodiments, distance D can vary.The space between annular rings 72, 74 is filled with a compressiblematerial, such that pressure exerted on outer annular ring 74 can causeouter annular ring 74 to deform, narrowing the distance D between innerand outer annular rings 72, 74. As described more fully below, inner andouter annular rings 72, 74 function as plates of a capacitor.Accordingly, the compressible material disposed between inner and outerannular rings 72, 74 can be chosen with suitable dielectric properties.In one embodiment, air is the compressible fluid used to fill the spacebetween inner and outer annular rings 72, 74, however, othercompressible dielectrics can be used, including, for example,elastomeric materials. Where air is used, non-conductive spacers can beincluded between inner and outer annular rings 72, 74 to prevent therings from electrically shorting. In some embodiments, the spacers arepositioned about the edge of the inner and outer annular rings 72, 74 soas to not inhibit compression of the outer annular ring 74.

Examples of conductive materials that can be used for inner and outerannular rings 72, 74 include Cu, Ag, Au, NiTi, and TiN. Any of a numberof conductive materials can be used to make inner and outer annularrings 72, 74, however, for intra-vascular applications, materials withgood biocompatibility are preferred.

Although the conductive plates of the pressure sensing apparatus areshown as cylindrical in this example, other hollow shapes can be used.For example four or six-sided concentric hollow members can be used,creating four or six capacitance regions, respectively.

In the example embodiment illustrated in FIG. 5, outer annular ring 74also includes slots 75A, 75B. Slots 75A, 758 define a region 76Atherebetween. In one embodiment, outer annular ring 74 includes fourslots, although a fewer or greater number of slots can be provided. Forexample, in some embodiments two slots are provided separating the outerannular ring 74 into two separate regions. In other embodiments, five ormore slots are provided, separating the outer annular ring 74 into fiveor more regions, respectively. The slots divide outer annular ring 74into a plurality of separate conductive areas, thereby defining separatecapacitive elements or plates. For example, in an embodiment where outerannular ring 74 in FIG. 5 includes four slots (only two of which arevisible in FIG. 5), four separate conductive regions 76A, 76B, 76C, 76Dare defined, creating four capacitors whose capacitance can varyindividually with pressure.

The capacitance of each region is given by:

$C = \frac{ɛ_{r}ɛ_{0}A}{D}$

Where A is the area of the plates, D is the distance between the plates,ε_(r) is the relative permittivity of the dielectric material betweenthe plates, and ε₀ is the permittivity of free space (ε₀≈8.854×10⁻¹²F/m).

For the sensor illustrated in FIG. 5, the area, A, is approximately thearea of the outer annular ring 74 between two slots (e.g., area A isvisible in FIG. 5). Because the area and the permittivities are known,the capacitance of the device can be measured to determine the distanceD between the plates. The device can be calibrated and the determineddistance D used to determine the amount of external pressure applied tothe outer annular ring 74.

While in some embodiments absolute pressure measurement can be used, forpurposes of other embodiments, what is important is measuring relativepressure changes. Relative pressure changes can be determined bymeasuring changes in capacitance. Changes in pressure on outer annularring 74 are sensed based on changes in capacitance of a region of thering that correspond to changes in the plate separation, D. A physicalchange in pressure causes the separation distance D to change by aquantity, Δ. Such changes can occur, for example by a change in bloodpressure, or by positioning of the ring against the vessel wall or othertissue. When such changes occur, the capacitance changes from

$C = {{\frac{ɛ_{r}ɛ_{0}A}{D}\mspace{14mu} {to}\mspace{14mu} C} = {\frac{ɛ_{r}ɛ_{0}A}{D + \Delta}.}}$

Accordingly, measuring changes in capacitance can provide informationregarding positioning of the device and changes in blood pressure. Notethat because the areas of the inner and outer annular rings 72, 74remain constant, and the permittivity of the material in the gap alsoremains constant, any change in capacitance can be attributed to achange in distance, D, between inner and outer annular rings 72, 74.Therefore, the equation above can be simplified to:

$C \propto \frac{1}{D}$

As stated above, multiple slots can be provided in outer annular ring 74to provide multiple individual capacitors about the circumference of thecylinder. FIG. 6A illustrates an example of a pressure measurementdevice 70 having four slots 75 (only two of which, 75A, 75B can be seenon the illustration), four areas 76 (only three of which 76A, 76B, 76Ccan be seen on the illustration) forming plates of four capacitiveelements, and a measuring circuit 95. Measuring circuit 95 can beimplemented using the circuits shown in FIGS. 6B and 6C, however, inother embodiments, other measuring circuits can be used.

In the example illustrated in FIG. 6A, there are four conductive paths82A, 82B, 82C and 82D each electrically connecting its respective outerplate 76A, 76B, 76C, 76C of the corresponding capacitive element.Switches 83 are provided to selectively switch one of the fourcapacitive elements to measuring circuit 95. Switches can be manuallyactuated or they can be controlled by algorithms (e.g., byevaluation/feedback algorithms 30) to select which capacitive element isbeing measured. In another embodiment, multiple measuring circuits canbe provided to allow simultaneous measurement of capacitive elementswithout the need for switching.

FIG. 6B is a diagram illustrating an exemplary simplified circuit thatcan be used to measure changes in capacitance C. Referring now to FIG.6B, in this example, a microcontroller 85 can be provided to generate asquare wave. The square wave output can be filtered by filter 86 togenerate a sinusoidal signal. Other signal generators can be used togenerate the sinusoidal signal. The capacitor to be measured (e.g., fromsensor 70) is switched into the amplifier circuit 87 by multiplexer 83.The value of the capacitance switched in to the amplifier circuit 87affects the amplitude of the output sinusoidal signal. Rectifier 88rectifies the sinsusoid to provide a positive amplitude signal V_(IN) tointegrator 89. Integrator 89 charges capacitor C_(f) over N cycles ofthe rectified signal and outputs a voltage V_(OUT) that corresponds tothe pressure value. Particularly,

$V_{OUT} = {{- \frac{1}{R_{i}C_{f}}}{\int{V_{IN}{dt}}}}$

FIG. 6C is a diagram illustrating another exemplary simplified circuitthat can be used to measure changes in capacitance C. This example usesa 555 timer IC 93 operating as an oscillator in the astable mode,although other oscillator circuits can be used. The variable capacitorprovided by the inner and outer annular rings 72, 74, separated by adistance D is illustrated at 90. In this example, a simple timer circuitis used to generate a signal to charge and discharge the capacitor 90.The capacitor 90 is charged by the voltage applied through resistors R1and R2. The capacitor 90 is discharged via the discharge pin DIS throughresistor R2. When capacitor 90 charges and the voltage across capacitor90 is greater than the control voltage (which with the 555 IC 93 can becontrolled by control voltage pin CTRL), the output OUT transitions to alow state and the capacitor is discharged via discharge pin DIS throughresistor R2. When the voltage across the capacitor 90 drops below acertain threshold (e.g., ½ of the control voltage), this voltage,applied to the trigger pin TR of IC 93, causes the output OUT totransition high and start a new timing interval. Accordingly, output pinOUT generates a square wave output whose frequency, f, varies as afunction of capacitance 90 and resistances R1 and R2. Particularly, thefrequency, f, of the output signal is given by the equation:

$f = \frac{1}{C*\left( {{R\; 1} + {2R\; 2}} \right)*{\ln (2)}}$

Accordingly, a microcontroller or other computing module can be used tomeasure the frequency, f, of the output signal and determine thecapacitance of capacitor 90. Note, that although the inner annular ring72 is shown as being connected to ground GND in this sample circuit, oneof ordinary skill in the art after reading this description willunderstand that the polarity of the inner and outer annular rings 72, 74can be reversed.

One or more pressure measurement devices 70 can be provided withtreatment device 12 or therapeutic assembly 21 to measure absolutepressure or changes in pressure. FIGS. 7A-7D provide examples of usingone or more pressure measurement devices (e.g., capacitance devices) 70proximal to therapeutic assembly 21 to provide pressure measurements.FIG. 7A illustrates a pressure measurement device 70 proximal to aballoon 118. Balloon 118 can be a cryo-ablation balloon, which can beused for cryogenic treatment. Balloon 118 can also be, for example, aballoon configured to position electrodes for RF ablation, a balloonwith electrodes disposed on its surface, a balloon used to place astent, a balloon used to clear blockages, or other therapeutic balloonused for treatment. FIG. 7B illustrates a pressure measurement device 70proximal to the distal end of a guide catheter 119. Catheter 119 can beany of a number of different types of catheter. FIG. 7C illustrates apressure measurement device 70 positioned on both the distal andproximal ends of a balloon 118. The configuration in FIG. 7C can beused, for example, to confirm the creation of an occlusion in thevessel. FIG. 7D illustrates a pressure measurement device 70 proximal tothe distal end of an RF ablation device 120. RF ablation device 120 inthis example includes a flexible tip 121 and an RF probe 122 to deliverRF energy to the treatment site. The configuration illustrated in FIG.7D can be used to provide real time blood pressure monitoring during RFablation.

FIGS. 8A-8C provide examples of the applications of pressure measurementdevices 70 in situ. FIG. 8A illustrates an example wherein a balloon 118is located in renal artery RA and a pressure measurement device 70 isprovided to measure blood pressure in the renal artery RA. Balloon 118could be, for example a balloon for neuromodulation such as acryo-ablation balloon, a balloon with RF electrodes to deliver RF energyto the tissue, or other balloon configured for neuromodulation.

FIG. 8B illustrates an example in which two pressure measurement devices70 are provided, one at each end of balloon 118 inflated in the renalartery RA. The pressure measurement devices 70 measure the bloodpressure at each end of the balloon 118. The measurement of asignificantly lower blood pressure on the distal side of balloon 118indicates a good occlusion. FIG. 8C illustrates an example in whichpressure measurement device 70 is incorporated into an RF ablationdevice to measure blood pressure during and immediately after a renalneuromodulation procedure in the renal artery RA. As these examplesserve to illustrate, there are number of applications for one or morepressure measurement devices to be provided at or proximal totherapeutic assembly 21.

In other embodiments, one or more pressure measurement devices 70 can becollocated with one or more electrodes (or other delivery devices) usedto deliver RF energy to the renal nerves. Consider an example where oneor more electrodes are disposed on a catheter for placement against thetarget tissue. The one or more electrodes can be positioned on acatheter tip for delivery to the treatment site. In other embodiments,one or more electrodes can be positioned on a shape-set delivery device(e.g., NiTi wire) that, when expanded, takes its shape to be positionedagainst the artery wall. As still a further example, the shape setdelivery device on which one or more electrodes are mounted can be ahelical support structure 22, such as that described above in FIGS. 3and 4. In other embodiments, one or more electrodes can be mounted onother structures for placement against the targeted tissue.

In the case of RF renal neuromodulation, electrode positioning isintended to cause the one or more electrodes to come into sufficientcontact with the artery wall such that RF energy can be appropriatelydelivered to the renal nerves. However, it can be difficult to determinewhether the support structure 22 is properly expanded and whethersufficient contact is made by the support structure 22 (and hence theelectrodes 24) with the artery wall. Accordingly, one or more pressuremeasurement devices 70 can be disposed on the catheter (or on supportstructure 22) and used to detect or measure correct apposition of therenal neuromodulation electrodes.

FIG. 9 is a diagram illustrating an example of a pressure sensorintegrated within an electrode in accordance with one embodiment of thetechnology described herein. Referring now to FIG. 9, an electrode 24has a conductive outer surface 91 and a hollow inner body region.Contact 93 is electrically connected to energy source or console 26 andcouples the RF energy (in the case of RF neuromodulation) to electrode24. A layer of insulation 94 is provided about the inner circumferenceor perimeter of electrode 24. The pressure sensor elements are disposedwithin the layer of insulation 94 to electrically isolate the pressuresensor elements from the electrode body.

In the illustrated example, a multi-region, annular capacitive sensor isused as the pressure sensor. An outer conductive surface 96 surrounds aninner conductive surface 97 with a gap between the two conductivesurfaces 96, 97. Inner conductive surface 97 is slotted or otherwiseseparated to create different conductive regions about the innerconductive surface 97. Similar to the embodiment shown in FIGS. 5 and6A, inner and outer conductive surfaces 96, 97 can be made ofcylindrical conductors disposed in coaxial relation to one another.Unlike the embodiment shown in FIGS. 5 and 6A, inner conductive surface97 is slotted and outer conductive surface 96 forms a continuouscylindrical conductor, however this configuration can be reversed. Theslots divide conductive surface 97 into a plurality of regions. Theexample of FIG. 9 includes four regions, but only three are visible inthe drawing.

Four conductive paths 102A, 102B, 102C and 102D each electricallyconnecting its respective region of the inner conductive surface 97.Switches 103 are provided to selectively switch one of the fourcapacitive elements to measuring circuit 95. Switches can be manuallyactuated or they can be controlled by algorithms (e.g., byevaluation/feedback algorithms 30) to select which capacitive element isbeing measured. In another embodiment, multiple measuring circuits canbe provided to allow simultaneous measurement of capacitive elementswithout the need for switching.

In various embodiments, outer conductive surface 96 can be continuous sothat only one lead 104 is needed from surface 96 to measure thecapacitances of the regions. In other embodiments, outer conductivesurface 96 can be segmented into different sections or regionscorresponding to the regions of inner conductive surface 97.

FIG. 10A is a diagram illustrating an example of a pre-shaped supportstructure 22 with a plurality of energy delivery elements 24. Supportstructure 22 can be, for example, a catheter tip, a shape set wire(e.g., shape set in a helical or other geometry), or other structureused to place and/or support energy delivery elements 24. For clarity ofillustration, support structure 22 is illustrated in an elongatedconfiguration, however, it will be understood by those of ordinary skillin the art upon reading this description that when expanded, supportstructure 22 can take on a desired shape (e.g., a helical shape) tocause the electrodes 24 to contact the arterial walls. For example,support structure 22 can be implemented using a helical structure asdescribed above with reference to FIGS. 3 and 4.

Because the feedback provided through over-the-wire and guide-wirecatheters (e.g., via feel or fluoroscopy) is generally not sufficient toinform the clinician whether good and proper contact of the electrodesis made with the arterial wall, additional feedback mechanisms can bebeneficial. Likewise, because in some embodiments the electrodes may bedisposed on one side of the support structure 22, knowledge of theorientation of the expanded support structure 22 can be important.Accordingly, in various embodiments, one or more pressure measurementdevices 70 can be disposed on the support structure 22 proximal to theelectrodes 24 to provide position sensing of the support structure 22and hence the electrodes 24.

FIG. 10B is a diagram illustrating an example in which a plurality ofpressure measurement devices 70 are disposed on support structure 22proximal to a plurality of electrodes 24. In the example illustrated inFIG. 10B, pressure measurement devices 70 are disposed between adjacentelectrodes 24. Where capacitive pressure measurement devices 70 areused, the pressure measurement devices 70 are electrically insulatedfrom the arterial wall via sheath 132. Sheath 132 is provided toprohibit the arterial wall from affecting the capacitance of pressuremeasurement devices 70. Additionally, control wires (not shown) areincluded to provide the RF signals necessary to stimulate electrodes 24,and sense wires (not shown) are included to electrically connect theconductive surfaces of pressure measurement devices 70 to the measuringcircuit (e.g., wires 82 in the embodiment illustrated in FIG. 6A). Inother embodiments, pressure measurement devices 70 include measuringcircuitry and wireless transmitters to transmit pressure measurements tothe monitoring system.

The example illustrated in FIG. 10B includes a plurality of electrodes24 distributed along the illustrated section of support structure 22.This example further shows pressure measurement devices 70 disposedbetween each adjacent pair of electrodes 24. In various embodiments, oneor more pressure measurement devices 70 is disposed adjacent to orwithin (e.g., FIG. 9) an electrode 24. Placing one or more pressuremeasurement devices 70 closely adjacent an electrode 24 allows thepressure measurement devices 70 to be used to sense the position andorientation of the electrode while reducing or eliminating effects ofany torsion in support structure 24. Although the example in FIG. 10Bshows electrodes and pressure measurement devices 70 closely spacedalong the entire length of the segment, other spacings can be used. Forexample, an electrode and one or more adjacent pressure measurementdevices 70 can be spaced about a helical support structure 22quarter-turn intervals, half-turn intervals, full-turn intervals, or atother spacing intervals.

The example of FIG. 10B is now described in terms of the examplepressure measurement device illustrated in FIGS. 5 and 6A. Capacitivepressure measurement device 70, as described above in FIGS. 5 and 6A,can be divided into a plurality of regions about the device.Accordingly, the capacitance of, and hence the pressure applied to, eachregion of the device can be measured separately. By measuring thecapacitance of a given region, the relative capacitances betweenregions, or changes in capacitance of one or more regions, themonitoring system (e.g., by evaluation/feedback algorithms 30) candetermine whether pressure is being applied to a particular region of aparticular pressure measurement device 70. During deployment andplacement in the vasculature, increased pressure above a nominalpressure in a particular region of a pressure measurement device 70 mayindicate that particular region of the device is contacting the vesselwall. A measurement of the change in capacitance above nominal, or theabsolute capacitance, can give an indication of the amount of pressurebeing applied against the vessel wall. Likewise, a sense in increasedpressure of a first region over that of other regions of the device canindicate that the first region is contacting the vessel wall.

Consider the example of FIG. 11, which is a cross-sectional view showinga pressure measurement device 70 mounted circumferentially about apre-shaped wire 130. In this example, an electrode 24 is disposed on asurface of wire 130. Also in this example, there are four slots 75 (notshown) in the outer surface 74 of pressure measurement device 70,effectively dividing the pressure measurement device 70 into fourregions. These four regions are labeled Region 1, Region 2, Region 3 andRegion 4. Accordingly, pressure measurement device 70 effectivelyincludes 4 capacitive elements, one corresponding to each region, whosecapacitances can be separately measured to detect the pressure applied,if any, in each region.

In an example application of this configuration, it would be desiredthat the support structure 22 be positioned such that the outer surface25 of the electrode 24 is put into contact with the vessel wall.Accordingly, during placement of the device in preparation for theprocedure, the system is configured to look for sufficient pressure inRegion 1 to indicate that surface 25 of electrode 24 is in propercontact with the vessel wall. As such, a monitoring system (e.g., byevaluation/feedback algorithms 30) can be used to detect the appropriatepressure in Region 1 and to alert the clinician when proper placement isattained. Audible, visual, or haptic feedback can be used to provide thedesired alert indicating proper placement.

Likewise, the monitoring system can also be used to detect whether oneof the other regions (e.g., Region 2, Region 3, or Region 4) iscontacting the vessel wall. If pressure measurements indicate that oneor more of the other regions is contacting the vessel wall instead ofRegion 1, the monitoring system can provide an indication to theclinician that contact is made but alignment or orientation is off. Thesystem can further be configured to indicate to the clinician whichregion is making contact so the clinician can determine what adjustmentsmay be necessary to achieve proper contact of electrode 24. For example,if the system determines that contact is being made with Region 4, thesystem can alert the user that Region 4 is contacting the vessel walland can instruct the user to rotate the orientation of the structure by90 degrees counterclockwise. As this illustrates, pressure measurementsof the various regions of a pressure sensor can be used to determineelectrode positioning and orientation. Particularly, the measurementscan indicate whether the desired surface 25 is contacting the vesselwall and whether the electrode 24 is lying flat against the tissue. Themeasurements can also indicate whether the electrode 24 is positioned onits edge or is otherwise not properly oriented. Because the pressuremeasurements can be used to determine orientation of the supportstructure 22 and electrode 24 relative to the vessel wall, a visualdisplay can be provided showing the clinician the orientation of thedevice on a display screen (e.g., display 33). With this visualinformation, the clinician can determine how to adjust orientation ofthe device to achieve proper contact.

In the case of embodiments using multiple pressure measurement devices70, similar positioning feedback mechanisms can be used for each of themultiple devices. Accordingly, with such embodiments, the clinician candetermine existence and quality of physical contact of the electrodewith the targeted tissue.

Also, because there are multiple regions, a pressure measurement device70 configured in this fashion can be used to sense placement of thedesired region against the vessel wall, and to sense patient bloodpressure via one or more of the other regions. Accordingly, simultaneousor sequential measurements can be used to determine placement and tomeasure patient blood pressure with a measurement device 70.

In some embodiments, impedance sensors are used in conjunction withpressure sensors to provide positioning feedback. Because the impedanceof blood is different from that of tissue, impedance measured at anelectrode will rise when it makes contact with tissue. Accordingly,impedance can be used to measure contact by measuring the rise inimpedance as an electrode goes from the blood pool to tissue. Howeverthe value of the rise in impedance can vary based on factors such astissue type, patient anatomy, varied blood flow, etc. Thus, it isdifficult to choose a threshold to universally use across patients todetermine contact with impedance alone. Accordingly, in someembodiments, impedance and pressure sensors are used to providepositioning feedback relative to tissue. This is now described in thecontext of a simple example. Consider an example of a helical supportstructure that can be expanded to contact the vessel wall. When thedevice is positioned in the artery, but before it is expanded ordeployed such that the electrodes are not making contact with tissue,reference impedance and pressure measurements are made and the resultrecorded. As the helical structure is being expanded, pressure ismonitored. When the pressure sensor indicates an increase in pressure,this signals contact of the support structure. Depending on theproximity of the pressure sensors to the electrodes, this could alsoprovide some indication of contact by the electrode. However, becausethe pressure sensors are adjacent the electrodes and they do not occupythe same space, contact by a sensor is not a guarantee that there iscontact by the electrode. Therefore, electrode contact can be confirmedby impedance measurements. Particularly, impedance can also be checkedand compared against the reference impedance measurement. A change inimpedance (e.g., a rise) in impedance (which can be measured, forexample, by measuring the current at the return) gives an indicationthat the electrode itself is making contact. Accordingly, using bothimpedance and pressure measurements can provide additional informationto the clinician about the electrode contact.

FIG. 12 is an operational flow diagram illustrating an example processfor using a pressure sensor to determine placement in accordance withone embodiment of the technology described herein. Referring now to FIG.12, at operation 141 the treatment device is deployed. For example, inthe case of RF ablation for renal neuromodulation, the devices deployedwith one or more electrodes positioned at the catheter tip to provide RFenergy for renal neuromodulation. In accordance with variousembodiments, one or more pressure sensors are included adjacent to theRF electrodes to allow position sensing. One example configuration forthis is that illustrated above with reference to FIG. 10B.

At operation 143, the nominal pressures of the pressure sensors in thebloodstream near the treatment site are measured and recorded. This canbe used to provide a reference pressure measurement for the one or morepressure sensors included with the device. In some embodiments,impedance measurements can also be made at this time to determine areference impedance measurement prior to deployment. At operation 145,the actuator is placed at the treatment site. For example, thepre-shaped wire can be deployed to position the electrodes against thevessel wall.

At operation 148, the pressures of the one or more pressure sensors aremeasured. This step can be performed continuously during placement ofthe actuator, or can be performed at periodic intervals to checkplacement. The goal of this step is to measure pressures to determinewhether or not placement against the vessel wall has been achieved. Forexample, as described above with reference to FIG. 11, measurement ofthe pressures at various regions of one or more pressure sensing devicescan be used to determine an orientation of the pressure sensing deviceas it is placed into contact with the vessel wall.

If pressure sensing determines a proper placement (e.g., properorientation) has been achieved, the operator is informed and theprocedure can commence. This is illustrated at operations 151 and 153.For example, a multi-region pressure sensor such as that described abovewith reference to FIG. 11 can be used to determine orientation of theassembly. If, on the other hand, pressure sensing operation indicatesthat proper placement has not been achieved, the operator is informedand the placement is adjusted in an attempt to achieve proper placement.This is illustrated at operations 151 and 155. In some embodiments,impedance measurements can also be made and compared against thereference impedance measurement to determine whether a change inimpedance indicates contact. Likewise, impedance measurements can alsobe made during the treatment process to determine whether changes inimpedance indicate the formation of lesions.

Feedback can be used for purposes other than apposition judgment. Insome embodiments, feedback is used to determine the effectiveness ofrenal neuromodulation treatment. For example, in the case of renalneuromodulation, one or more various patient metrics can be measured andused to determine the efficacy of the ablation and/or the effectivenessof applied treatment. FIG. 13 is a diagram illustrating an exampleprocess for using feedback to determine the effectiveness of treatmentin accordance with one embodiment of the systems and methods describedherein. Referring now to FIG. 13, at operation 103 one or more patientmetrics are measured and recorded. For example, metrics such as patientblood pressure and norepinephrine levels can be measured. Other metricsindicating whether a lesion was successfully formed can include tissuetemperature, impedance, and blood flow.

In further embodiments, blood flow can be monitored in real time and theflow rate information used to inform the process. For example, bloodflow can be calculated using pressure measurements from a plurality ofsensors separated from one another by known distances and positionedalong the axial length of the artery. The system can be configured tomeasure pressure changes across the plurality of sensors and detect thetimes at which such changes occur. For example, the time at which ameasured rise, in pressure occurs at one sensor is compared to the timeat which a corresponding rise in pressure occurs at another sensor, anda time difference calculated. The blood flow rate can then be determinedby dividing the known distance between those two sensors by thecalculated time difference.

Blood flow can have a significant effect on electrode temperature andthe ability to deliver RF energy at certain power levels before damagingthe artery wall. In addition, blood flow could be an indication that thevessel is constricting and lesions are being formed. Accordingly, thepower delivery algorithm can be configured to measure blood flow ratesand adjust power levels accordingly. For example, in high-blood-flowconditions, power can be increased to account for increased coolingprovided by the higher flow rate. Likewise, in low-blood-flowconditions, power can be reduced. The process for measuring blood flowrates could include, for example, taking an initial blood-flowmeasurement to establish a reference. With the reference established,periodic measurements can be taken throughout the procedure and comparedto the reference to monitor changes. The system can be configured toalert the clinician where the changes exceed a predetermined threshold,in response to which the procedure may be terminated. In anotherembodiment, the procedure can be performed (e.g., for a predeterminedtime) and blood-flow measurements taken before or after a procedurecould be used to give the clinician a possible indication of treatmentefficacy. It is noted that an increased rate of blood flow could be anindication that a vessel is constricting due to the formation oflesions.

At operation 106, the procedure is performed. For example, in oneembodiment the procedure can be a renal neuromodulation procedureperformed using a system such as, for example, system 1 illustrated inFIG. 1. Although the procedure performed with the example method of FIG.13 can be any of a number of different procedures, the process isdescribed herein in terms of a renal neuromodulation procedure.Description in these terms is provided for ease of discussion only, andafter reading this description, one of ordinary skill in the art willunderstand how the systems and methods described herein can beimplemented with any of a number of different medical procedures.Examples of such medical procedures include, without limitationdenervation or neuromodulation of non-renal targets or ablations ofvarious anatomical elements.

At operation 108, the patient metrics are again measured. Thissubsequent measurement can be performed at one or more intervalsthroughout the procedure, and it can be performed at the conclusion ofthe procedure. Preferably, the patient metrics measured at operation 108during and after the procedure are the same metrics measured before theprocedure at operation 103.

At operation 111, the measurement or measurements made at operation 108are compared with the corresponding measurement(s) made at operation 108to determine the efficacy of the treatment. For example, in the case ofrenal neuromodulation, one metric for determining the effectiveness ofthe treatment is the patient's systolic blood pressure. This is becausein people with hypertension, the renal nerves are hyperactive, whichraises blood pressure. Denervation of the renal sympathetic nerve canresult in a large and highly significant reduction in systolic bloodpressure.

If the desired level of change in the one or more metrics is met, theefficacy of the treatment is verified, the treatment can be concluded,and the final measurements can be recorded. This is illustrated byoperations 114 and 116. On the other hand, if the desired level ofchange in the one or more metrics is not met, the clinician maydetermine to continue the procedure as illustrated by flow line 118.Continuing with the above example, in the case of renal neuromodulation,if the measurement shows the desired level of reduction in the patient'sblood pressure, the treatment can be suspended. If the desired level ofreduction is not met, the procedure may be continued. It is noted thatimmediate reductions in blood pressure do not always accompany asuccessful renal neuromodulation procedure.

In the above-described example, measurements made during orpost-procedure are compared with prior measurements to determine whetherthe desired level of change in condition has been achieved. In otherembodiments, measurements are made to determine whether a predeterminedtarget or objective has been met. For example, in the case of treatinghypertension using renal neuromodulation, blood pressure measurementsmade during or post-procedure can be evaluated against a target bloodpressure level to determine the efficacy of the treatment in real time.

In some embodiments, the measurements can be made continuously or atperiodic or other intervals and evaluation/feedback algorithms 31 can beused to determine the results. Audible alerts, display cues, hapticfeedback or other techniques can be used to alert the physician,health-care worker or other clinician when the desired treatment goalshave been achieved. For example, the system can be configured to sound achime or other audible alert when the desired blood-pressure level ismet, or to cause handle 34 to gently vibrate. Likewise, the system canbe configured to display the blood pressure on screen 33 for visualfeedback of actual measurements.

Although the above examples are described in terms of the pressuremeasurement device 70 illustrated in FIG. 5, the system is not limitedfor use with this device. Indeed, other pressure measurement devices canbe used including, for example, microelectromechanical systems (MEMS)devices and other pressure sensors. One example of a MEMS device that issuitable for use as a pressure sensor with the systems and methodsdisclosed herein are wireless pressure sensors provided by CardioMEMs,Inc., located at 387 Technology Circle NW in Atlanta, Ga. 30313. Also,although some examples set forth above describe mounting one or moreelectrodes and sensors on a pre-shaped core, one of ordinary skill inthe art after reading this description will appreciate that otherdelivery mechanisms or applicators can be used with the technologydescribed herein. Likewise, although the actuator is described invarious examples as an RF electrode, one of ordinary skill in the artafter reading this description will appreciate that the technologydescribed herein can be used to facilitate the positioning of otheractuators, such as temperature probes, heat- or cryo-tips, ultrasonictransducers, and so on.

Where components or modules of the invention are implemented in whole orin part using software, in one embodiment, these software elements canbe implemented to operate with a computing or processing module capableof carrying out the functionality described with respect thereto. Oneexample of a computing module is shown in FIG. 14. Various embodimentsare described in terms of this example-computing module 200. Afterreading this description, it will become apparent to a person skilled inthe relevant art how to implement the invention using other computingmodules or architectures.

Referring now to FIG. 14, computing module 200 may represent, forexample, computing or processing capabilities found within desktop,laptop and notebook computers; hand-held computing devices (PDA's, smartphones, tablets, cell phones, palmtops, etc.); mainframes,supercomputers, workstations or servers; or any other type ofspecial-purpose or general-purpose computing devices as may be desirableor appropriate for a given application or environment. Computing module200 might also represent computing capabilities embedded within orotherwise available to a given device.

Computing module 200 might include, for example, one or more processors,controllers, control modules, or other processing devices, such as aprocessor 204. Processor 204 might be implemented using ageneral-purpose or special-purpose processing engine such as, forexample, a microprocessor, controller, or other control logic. In theillustrated example, processor 204 is connected to a bus 202, althoughany communication medium can be used to facilitate interaction withother components of computing module 200 or to communicate externally.

Computing module 200 might also include one or more memory modules,simply referred to herein as main memory 208. For example, preferablyrandom access memory (RAM) or other dynamic memory, might be used forstoring information and instructions to be executed by processor 204.Main memory 208 might also be used for storing temporary variables orother intermediate information during execution of instructions to beexecuted by processor 204. Computing module 200 might likewise include aread only memory (“ROM”) or other static storage device coupled to bus202 for storing static information and instructions for processor 204.

The computing module 200 might also include one or more various forms ofinformation storage mechanism 210, which might include, for example, amedia drive 212 and a storage unit interface 220. The media drive 212might include a drive or other mechanism to support fixed or removablestorage media 214. For example, a hard disk drive, a floppy disk drive,a magnetic tape drive, an optical disk drive, a CD or DVD drive (R orRW), or other removable or fixed media drive might be provided.Accordingly, storage media 214 might include, for example, a hard disk,a floppy disk, magnetic tape, cartridge, optical disk, a CD or DVD, orother fixed or removable medium that is read by, written to or accessedby media drive 212. As these examples illustrate, the storage media 214can include a computer usable storage medium having stored thereincomputer software or data.

In alternative embodiments, information storage mechanism 210 mightinclude other similar instrumentalities for allowing computer programsor other instructions or data to be loaded into computing module 200.Such instrumentalities might include, for example, a fixed or removablestorage unit 222 and an interface 220. Examples of such storage units222 and interfaces 220 can include a program cartridge and cartridgeinterface, a removable memory (for example, a flash memory or otherremovable memory module) and memory slot, a PCMCIA slot and card, andother fixed or removable storage units 222 and interfaces 220 that allowsoftware and data to be transferred from the storage unit 222 tocomputing module 200.

Computing module 200 might also include a communications interface 224.Communications interface 224 might be used to allow software and data tobe transferred between computing module 200 and external devices.Examples of communications interface 224 might include a modem orsoftmodem, a network interface (such as an Ethernet, network interfacecard, WiMedia, IEEE 802.XX or other interface), a communications port(such as for example, a USB port, IR port, RS232 port Bluetooth®interface, or other port), or other communications interface. Softwareand data transferred via communications interface 224 might typically becarried on signals, which can be electronic, electromagnetic (whichincludes optical) or other signals capable of being exchanged by a givencommunications interface 224. These signals might be provided tocommunications interface 224 via a channel 228. This channel 228 mightcarry signals and might be implemented using a wired or wirelesscommunication medium. Some examples of a channel might include a phoneline, a cellular link, an RF link, an optical link, a network interface,a local or wide area network, and other wired or wireless communicationschannels.

In this document, the terms “computer program medium” and “computerusable medium” are used to generally refer to media such as, forexample, main memory 208, storage unit interface 220, storage media 214,and channel 228. These and other various forms of computer program mediaor computer usable media may be involved in carrying one or moresequences of one or more instructions to a processing device forexecution. Such instructions embodied on the medium, are generallyreferred to as “computer program code” or a “computer program product”(which may be grouped in the form of computer programs or othergroupings). When executed, such instructions might enable the computingmodule 200 to perform features or functions of the present disclosure asdiscussed herein.

III. Pertinent Anatomy and Physiology

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated with renalneuromodulation. For example, as mentioned previously, severalproperties of the renal vasculature may inform the design of treatmentdevices and associated methods for achieving renal neuromodulation viaintravascular access, and impose specific design requirements for suchdevices. Specific design requirements may include accessing the renalartery, facilitating stable contact between the energy delivery elementsof such devices and a luminal surface or wall of the renal artery,and/or effectively modulating the renal nerves with the neuromodulatoryapparatus.

A. The Sympathetic Nervous System

The Sympathetic Nervous System (SNS) is a branch of the autonomicnervous system along with the enteric nervous system and parasympatheticnervous system. It is always active at a basal level (called sympathetictone) and becomes more active during times of stress. Like other partsof the nervous system, the sympathetic nervous system operates through aseries of interconnected neurons. Sympathetic neurons are frequentlyconsidered part of the peripheral nervous system (PNS), although manylie within the central nervous system (CNS). Sympathetic neurons of thespinal cord (which is part of the CNS) communicate with peripheralsympathetic neurons via a series of sympathetic ganglia. Within theganglia, spinal cord sympathetic neurons join peripheral sympatheticneurons through synapses. Spinal cord sympathetic neurons are thereforecalled presynaptic (or preganglionic) neurons, while peripheralsympathetic neurons are called postsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to things as diverse as pupildiameter, gut motility, and urinary output. This response is also knownas sympatho-adrenal response of the body, as the preganglionicsympathetic fibers that end in the adrenal medulla (but also all othersympathetic fibers) secrete acetylcholine, which activates the secretionof adrenaline (epinephrine) and to a lesser extent noradrenaline(norepinephrine). Therefore, this response that acts primarily on thecardiovascular system is mediated directly via impulses transmittedthrough the sympathetic nervous system and indirectly via catecholaminessecreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 15, the SNS provides a network of nerves that allowsthe brain to communicate with the body. Sympathetic nerves originateinside the vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons should travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia. The cell that sends its fiberis called a preganglionic cell, while the cell whose fiber leaves theganglion is called a postganglionic cell. As mentioned previously, thepreganglionic cells of the SNS are located between the first thoracic(T1) segment and third lumbar (L3) segments of the spinal cord.Postganglionic cells have their cell bodies in the ganglia and sendtheir axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As shown in FIG. 16, the kidney is innervated by the renal plexus (RP),which is intimately associated with the renal artery. The renal plexus(RP) is an autonomic plexus that surrounds the renal artery and isembedded within the adventitia of the renal artery. The renal plexus(RP) extends along the renal artery until it arrives at the substance ofthe kidney. Fibers contributing to the renal plexus (RP) arise from theceliac ganglion, the superior mesenteric ganglion, the aorticorenalganglion and the aortic plexus. The renal plexus (RP), also referred toas the renal nerve, is predominantly comprised of sympatheticcomponents. There is no (or at least very minimal) parasympatheticinnervation of the kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus (RP) and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing overactivity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output, andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well known adverse consequences of chronic sympatheticover activity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

i. Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na+) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

ii. Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” may induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 17A and 17B, this afferentcommunication might be from the kidney to the brain or might be from onekidney to the other kidney (via the central nervous system). Theseafferent signals are centrally integrated and may result in increasedsympathetic outflow. This sympathetic drive is directed towards thekidneys, thereby activating the RAAS and inducing increased reninsecretion, sodium retention, volume retention and vasoconstriction.Central sympathetic over activity also impacts other organs and bodilystructures innervated by sympathetic nerves such as the heart and theperipheral vasculature, resulting in the described adverse effects ofsympathetic activation, several aspects of which also contribute to therise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renalneuromodulation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Neuromodulation

As provided above, renal neuromodulation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal neuromodulationmight also be useful in treating other conditions associated withsystemic sympathetic hyperactivity. Accordingly, renal neuromodulationmay also benefit other organs and bodily structures innervated bysympathetic nerves. For example, as previously discussed, a reduction incentral sympathetic drive may reduce the insulin resistance thatafflicts people with metabolic syndrome and Type II diabetics.Additionally, patients with osteoporosis are also sympatheticallyactivated and might also benefit from the down regulation of sympatheticdrive that accompanies renal neuromodulation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus (RP), which is intimately associated with aleft and/or right renal artery, may be achieved through intravascularaccess. As FIG. 18A shows, blood moved by contractions of the heart isconveyed from the left ventricle of the heart by the aorta. The aortadescends through the thorax and branches into the left and right renalarteries. Below the renal arteries, the aorta bifurcates at the left andright iliac arteries. The left and right iliac arteries descend,respectively, through the left and right legs and join the left andright femoral arteries.

As FIG. 18B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or the right renal artery. This comprises an intravascular paththat offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, the brachial, or the axillaryartery may be utilized in select cases. Catheters introduced via theseaccess points may be passed through the subclavian artery on the leftside (or via the subclavian and brachiocephalic arteries on the rightside), through the aortic arch, down the descending aorta and into therenal arteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus (RP) may beachieved in accordance with the present technology through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systems,and methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or the right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, consistent positioning and appropriatecontact force applied by the energy delivery element to the vessel wallare important for predictability. However, navigation is impeded by thetight space within a renal artery, as well as tortuosity of the artery.Furthermore, establishing consistent contact is complicated by patientmovement, respiration, and/or the cardiac cycle because these factorsmay cause significant movement of the renal artery relative to theaorta, and the cardiac cycle may transiently distend the renal artery(i.e., cause the wall of the artery to pulse).

Even after accessing a renal artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventia of the artery should be safelymodulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant fromthe luminal surface of the artery. Sufficient energy should be deliveredto or heat removed from the target renal nerves to modulate the targetrenal nerves without excessively cooling or heating the vessel wall tothe extent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. A potential clinical complicationassociated with excessive heating is thrombus formation from coagulatingblood flowing through the artery. Given that this thrombus may cause akidney infarct, thereby causing irreversible damage to the kidney,thermal treatment from within the renal artery should be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the renal artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment site, maybe important in applying energy (e.g., heating thermal energy) and/orremoving heat from the tissue (e.g., cooling thermal conditions) fromwithin the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the energy delivery elementwithin the renal artery since location of treatment may also impactclinical efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery. Insome situations, full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to renal arterystenosis. Therefore, the formation of more complex lesions along alongitudinal dimension of the renal artery via the mesh structuresdescribed herein and/or repositioning of the neuromodulatory apparatusto multiple treatment locations may be desirable. It should be noted,however, that a benefit of creating a circumferential ablation mayoutweigh the potential of renal artery stenosis or the risk may bemitigated with certain embodiments or in certain patients and creating acircumferential ablation could be a goal. Additionally, variablepositioning and repositioning of the neuromodulatory apparatus may proveto be useful in circumstances where the renal artery is particularlytortuous or where there are proximal branch vessels off the renal arterymain vessel, making treatment in certain locations challenging.Manipulation of a device in a renal artery should also considermechanical injury imposed by the device on the renal artery. Motion of adevice in an artery, for example by inserting, manipulating, negotiatingbends and so forth, may contribute to dissection, perforation, denudingintima, or disrupting the interior elastic lamina.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time should be avoided to prevent injury to thekidney such as ischemia. It could be beneficial to avoid occlusion alltogether or, if occlusion is beneficial to the embodiment, to limit theduration of occlusion, for example to 2-5 minutes.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility; and (f) the take-off angle of a renal arteryrelative to the aorta. These properties will be discussed in greaterdetail with respect to the renal arteries. However, dependent on theapparatus, systems and methods utilized to achieve renalneuromodulation, such properties of the renal arteries, also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery shouldconform to the geometry of the artery. Renal artery vessel diameter,DRA, typically is in a range of about 2-10 mm, with most of the patientpopulation having a DRA of about 4 mm to about 8 mm and an average ofabout 6 mm. Renal artery vessel length, LRA, between its ostium at theaorta/renal artery juncture and its distal branchings, generally is in arange of about 5-70 mm, and a significant portion of the patientpopulation is in a range of about 20-50 mm. Since the target renalplexus is embedded within the adventitia of the renal artery, thecomposite Intima-Media Thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment is important to reach the target neural fibers, thetreatment should not be too deep (e.g., >5 mm from inner wall of therenal artery) to avoid non-target tissue and anatomical structures suchas the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta, induced by respirationand/or blood flow pulsatility. A patient's kidney, which located at thedistal end of the renal artery, may move as much as 4″ cranially withrespiratory excursion. This may impart significant motion to the renalartery connecting the aorta and the kidney, thereby requiring from theneuromodulatory apparatus a unique balance of stiffness and flexibilityto maintain contact between the thermal treatment element and the vesselwall during cycles of respiration. Furthermore, the take-off anglebetween the renal artery and the aorta may vary significantly betweenpatients, and also may vary dynamically within a patient, e.g., due tokidney motion. The take-off angle generally may be in a range of about30 degrees-135 degrees.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample only, and not of limitation. Likewise, the various diagrams maydepict an example architectural or other configuration for theinvention, which is done to aid in understanding the features andfunctionality that can be included in the invention. The invention isnot restricted to the illustrated example architectures orconfigurations, but the desired features can be implemented using avariety of alternative architectures and configurations. Indeed, it willbe apparent to one of skill in the art how alternative functional,logical or physical partitioning and configurations can be implementedto implement the desired features of the present invention. Also, amultitude of different constituent module names other than thosedepicted herein can be applied to the various partitions. Additionally,with regard to flow diagrams, operational descriptions and methodclaims, the order in which the steps are presented herein shall notmandate that various embodiments be implemented to perform the recitedfunctionality in the same order unless the context dictates otherwise.

Although the invention is described above in terms of various exemplaryembodiments and implementations, it should be understood that thevarious features, aspects and functionality described in one or more ofthe individual embodiments are not limited in their applicability to theparticular embodiment with which they are described, but instead can beapplied, alone or in various combinations, to one or more of the otherembodiments of the invention, whether or not such embodiments aredescribed and whether or not such features are presented as being a partof a described embodiment. Thus, the breadth and scope of the presentinvention should not be limited by any of the above-described exemplaryembodiments.

Terms and phrases used in this document, and variations thereof, unlessotherwise expressly stated, should be construed as open ended as opposedto limiting. As examples of the foregoing: the term “including” shouldbe read as meaning “including, without limitation” or the like; the term“example” is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; the terms “a” or“an” should be read as meaning “at least one,” “one or more” or thelike; and adjectives such as “conventional,” “traditional,” “normal,”“standard,” “known” and terms of similar meaning should not be construedas limiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or standard technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. The use of theterm “module” does not imply that the components or functionalitydescribed or claimed as part of the module are all configured in acommon package. Indeed, any or all of the various components of amodule, whether control logic or other components, can be combined in asingle package or separately maintained and can further be distributedin multiple groupings or packages or across multiple locations.

Additionally, the various embodiments set forth herein are described interms of exemplary block diagrams, flow charts and other illustrations.As will become apparent to one of ordinary skill in the art afterreading this document, the illustrated embodiments and their variousalternatives can be implemented without confinement to the illustratedexamples. For example, block diagrams and their accompanying descriptionshould not be construed as mandating a particular architecture orconfiguration.

What is claimed is:
 1. An apparatus for measuring blood pressure of apatient during a neuromodulation treatment, comprising: a therapeuticassembly configured for intravascular delivery to a treatment site; anenergy delivery element disposed on the therapeutic assembly andconfigured to be positioned against a vessel wall to deliverneuromodulation energy at the treatment site; and a pressure sensorhaving a plurality of pressure sensitive regions, the pressure sensorbeing configured to measure the blood pressure of the patient.
 2. Theapparatus of claim 1, wherein the pressure sensor includes a firstconductive annular ring, a second conductive annular ring and aplurality of non-conductive areas on the second conductive annular ring.3. The apparatus of claim 1, wherein the plurality of pressure sensitiveregions are configured to sense pressure in a plurality of directionsabout the energy delivery element.
 4. The apparatus according to claim1, wherein the energy delivery element includes a plurality of energydelivery elements.
 5. The apparatus according to claim 1, wherein thepressure sensor includes a capacitive pressure sensor.
 6. The apparatusaccording to claim 1, wherein the therapeutic assembly includes anelongated support structure configured to take a pre-determined shapeupon deployment in a vessel, wherein the energy delivery element isdisposed in a predetermined orientation on the elongated supportstructure.
 7. The apparatus according to claim 6, wherein the elongatedsupport structure is shaped in a helical geometry.
 8. The apparatusaccording to claim 1, wherein the therapeutic assembly is furtherconfigured to be expanded or deployed to a position proximal thetreatment site.
 9. An apparatus for measuring the blood pressure of apatient during a neuromodulation treatment, comprising: a therapeuticassembly configured for intravascular delivery to a treatment site; anenergy delivery element disposed on the therapeutic assembly andconfigured to be positioned against a vessel wall to deliverneuromodulation energy at the treatment site; and a pressure sensorhaving a plurality of pressure sensitive regions, the pressure sensorbeing configured to measure the blood pressure of the patient, theplurality of pressure sensitive regions being configured to sensepressure in a plurality of directions about the energy delivery element.10. The apparatus of claim 9, wherein the pressure sensor includes afirst conductive annular ring, a second conductive annular ring and aplurality of non-conductive areas on the second conductive annular ring.11. The apparatus according to claim 1, wherein the pressure sensorincludes a capacitive pressure sensor.
 12. The apparatus according toclaim 1, wherein the therapeutic assembly includes an elongated supportstructure configured to take a pre-determined shape upon deployment in avessel, wherein the energy delivery element is disposed in apredetermined orientation on the elongated support structure.
 13. Theapparatus according to claim 6, wherein the elongated support structureis shaped in a helical geometry.
 14. An apparatus according to claim 1,wherein the therapeutic assembly is further configured to be expanded ordeployed to a position proximal the treatment site.
 15. An apparatus formeasuring the blood pressure of a patient during a neuromodulationtreatment, comprising: a therapeutic assembly configured firintravascular delivery to a treatment site; an energy delivery elementdisposed on the therapeutic assembly and configured to be positionedagainst a vessel wall to deliver neuromodulation energy at the treatmentsite; and a pressure sensor being configured to measure the bloodpressure of the patient, the plurality of pressure sensitive regionsbeing configured to sense pressure in a plurality of directions aboutthe energy delivery element.
 16. The apparatus of claim 15, wherein thepressure sensor is integrated with the energy delivery element.
 17. Theapparatus of claim 16, further comprising: a layer of insulationprovided about an inner surface of the energy delivery element andconfigured to electrically isolate the pressure sensor from the energydelivery element.
 18. The apparatus of claim 15, wherein the pressuresensor is a pressure measurement device, wherein the pressuremeasurement device has a first annular ring and a second annular ring,wherein the first annular ring and the second annular ring are assembledin a coaxial configuration forming a hollow cylinder, wherein the firstannular ring and the second annular ring are made of a conductivematerial.
 19. The apparatus of claim 18, wherein the second annular ringhas a diameter greater than that of the first annular ring.
 20. Theapparatus of claim 18, wherein the first annular ring and the secondannular ring have a space in between that is filled with a compressiblematerial, such that pressure exerted on the second annular ring willcause the second annular ring to deform.